RNA interference (RNAi) with the use of small interfering RNA (siRNA) has been proposed as a highly effective therapy for myriad diseases including cancer and inflammatory diseases. However, despite nearly two decades of intense research, siRNA therapeutics have demonstrated limited success in translation to clinical applications due to poor cellular uptake and instability of free siRNA in serum. Cationic lipids and polymers have been successfully employed for siRNA transfection, but can exhibit unacceptable cytotoxicity and cause generation of reactive oxygen species (ROS) and Ca+2 leakage. In addition, cell penetrating peptide (CPP) based siRNA transfection agents, although showing promise with respect to reducing cytotoxicity, have not achieved the high efficiency of traditional lipidic transfection agents due to lysosomal trapping.
Therefore, there is a need in the art for new classes of therapeutic siRNA compositions and siRNA transfection agents capable of efficient cellular uptake and delivery into the cytoplasm for treating diseases.